This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Accurate control of the number of centrosomes, the major microtubule- organizing centers of animal cells, is critical for the maintenance of genomic integrity. Abnormalities in centrosome number can promote errors in spindle formation that lead to subsequent chromosome missegregation and extra centrosomes are found in many cancers. Centrosomes are comprised of a pair of centrioles surrounded by amorphous pericentriolar material and centrosome duplication is controlled by centriole replication. Polo-like kinase 4 (Plk4) plays a key role in initiating centriole duplication and overexpression of Plk4 promotes centriole overduplication and the formation of extra centrosomes. Recently, we showed that kinase active Plk4 is inherently unstable and targeted for degradation. Using mass spectrometry we demonstrated that Plk4 multiply self-phosphorylates within a 24 amino-acid ?phosphodegron" and that phosphorylation of multiple sites within this region is required for Plk4 instability. We continue to investigate how Plk4 auto-regulated instability acts to self-limits Plk4 activity so as to prevent centrosome amplification and genomic instability.